This invention provides an improved process for preparing intermediates useful in the preparation of tricyclic compounds known as antihistamines and as inhibitors of farnesyl protein transferase (FPT). In particular, the compounds of this invention are useful in the preparation of antihistamines such as those disclosed in U.S. Pat. Nos. 4,282,233 and 5,151,423, and of FPT inhibitors disclosed in PCT Publication No. WO97/23478, published Jul. 3, 1997.
This invention provides a process for preparing a compound having the formula: 
wherein R, R1, R2, R3, and R4 are independently selected from the group consisting of H, Br, Cl, F, alkyl, or alkoxy, said process comprising:
(A) reacting a compound having the formula 
wherein RA, RB, RC, RD, and RE are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R5 is aryl or heteroaryl, with
a dehydrating agent to produce an imine having the formula: 
(B) hydrolyzing the imine produced in step (A) to produce the compound having formula (I).
This invention also provides novel intermediates having the formula 
wherein RA, RB, RC, RD, and RE are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R5 is aryl or heteroaryl.
This invention further provides a process for preparing a compound having the formula: 
comprising:
reacting a compound having the formula: 
with NH2R5 in the presence of a palladium catalyst, carbon monoxide, a base, and an ether selected from the group consisting of: ethylene glycol dimethyl ether (i.e., CH3OCH2CH2OCH3); 2-methoxyethyl ether (i.e, CH3OCH2CH2OCH2CH2OCH3); and triethylene glycol dimethyl ether (i.e, CH3OCH2CH2OCH2CH2OCH2CH2OCH3), wherein X is H, Br, Cl, or F, and R5 is aryl or heteroaryl. The compounds of formula III can be reacted with compounds having the formula 
wherein U is Br or Cl and RB, RC, RD, and RE are as defined above, in the presence of a strong base to provide compounds having the formula II, wherein RA is Br, Cl or F.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched hydrocarbon chains of 1 to 6 carbon atoms.
xe2x80x9cHaloxe2x80x9d refers to fluorine, chlorine, bromine or iodine radicals.
xe2x80x9cArylxe2x80x9d means phenyl; benzyl; or a polyaromatic ring (e.g., napthyl), each of the foregoing being optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkoxy, and halo.
xe2x80x9cHeteroarylxe2x80x9d means a 5- or 6-membered aromatic ring having one or two nitrogen atoms, e.g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl.
xe2x80x9cAcxe2x80x9d refers to acetyl.
xe2x80x9cEtxe2x80x9d refers to xe2x80x94C2H5.
xe2x80x9cPhxe2x80x9d refers to phenyl.
The present process is a significant improvement over prior art processes for preparing the tricyclic ketone of formula (I). For example, U.S. Pat. No. 4,731,447 discloses the following process: 
In contrast to this process, in which the product from the hydrolysis step must be isolated and purified prior to the next step (the Friedel-Crafts cyclization), the present process for preparing compounds of formula (I) offers a more simplified synthesis that can be carried out in one pot.
PCT Publication WO96/31478, published Oct. 10, 1996, discloses the following process: 
In this process, a tert-butyl substituted compound is reacted with POCl3 in toluene at reflux to form the nitrile, the nitrile is reacted with CF3SO3H to form an imine, and the imine is hydrolyzed to form the ketone. Again, in contrast to this process, which is a two-pot process, because the nitrile must be isolated and purified prior to reaction with CF3SO3H, the present process can be carried out in one pot.
The compounds prepared by the present process are useful as intermediates in the procedures described in PCT Publication No. WO97/23478 and U.S. Pat. No. 5,151,423 to obtain the desired compounds wherein the piperidinyl ring is N-substituted. Using those procedures, the compounds of the present invention are reacted with a substituted piperidine of the formula 
wherein L1 is a leaving group selected from the group consisting of Cl and Br, to obtain a compound of the formula 
This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form. The piperidinyl nitrogen can then be reacted with a variety of compounds, e.g., an acyl compound such as an ester or acyl chloride to form the desired amide.
Alternatively, when chiral FPT inhibitors, such as those described in PCT Publication No. WO97/23478 are desired, the compounds made by the present process may be reduced by treating with Zn and 2 equivalents of trifluoroacetic acid in acetic anhydride to remove the carbonyl oxygen. The reduced compound can then be reacted with about 3.5 equivalents of lithium diisopropylamide, about 1.3 equivalents of quinine or a compound of the formula 
about 1.2 equivalents of 4-mesyl-N-Boc-piperidine, and about 1.1 equivalents of water in toluene to form the following chiral compound: 
This chiral compound can then be deprotected by treatment with acid (e.g., H2SO4), reacted with a suitable acid (e.g., N-acetyl-L-phenylalanine) to form a stable salt, and the stable salt can then be acylated with the desired acyl group.
Compounds of formula (I) can be converted to other compounds of formula (I) by methods known in the art, i.e., compounds wherein R, R1, R2, R3 or R4 is hydrogen can be converted to the corresponding compounds wherein R, R1, R2, R3 or R4 is halogen. Such procedures are shown in W097/23478, wherein, for example, a compound wherein R2 is Cl, R1, R3 and R4 are hydrogen and the piperidinyl nitrogen is protected by a xe2x80x94COOCH2CH3 group is reacted with KNO3, the resulting nitro-substituted compound is reduced to the amine, the resulting compound is reacted with Br2 and the amino group is removed to obtain a compound wherein R2 is Cl, R4 is Br and R1 and R3 are hydrogen.
Preferred compounds of formula (I) are those in which R2 is Cl, Br or F, more preferably Cl or Br, most preferably, Cl. Another group of preferred compounds are those in which R, R1, R3 and R4 are each hydrogen, and R2 is Cl, Br or F, more preferably Cl or Br, most preferably, Cl. Still another group of preferred compounds are those in which R1, R3, and R4 are each hydrogen and R and R2 are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br and R2 is Cl. Yet another group of preferred compounds are those in which R1 and R3 are each hydrogen, and R, R2 and R4 are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br, R2 is Cl and R4 is Br. These preferred compounds may be made from compounds of formula (II) having correspondingly positioned halo substituents. It will be appreciated by those skilled in the art that when the compounds of formula (II) have iodo substituents, those iodo substituents are displaced by H when the present process is carried out.
R5 is preferably aryl, most preferably, phenyl, 4-methoxyphenyl, 4-chlorophenyl, or 3-chlorophenyl.
The dehydrating agent is preferably selected from the group consisting of P2O5, P2O3, P2O3Cl4, POCl3, PCl3, PCl5, C6H6P(O)Cl2 (phenyl phosphonic dichloride), PBr3, PBr5, SOCl2, SOBr2, COCl2, H2SO4, super acids, and anhydrides of super acids. More preferably, the dehydrating agent is selected from P2O5, P2O3Cl4, PBr3, PCl5, POCl3, C6H6P(O)Cl2, (CF3SO2)2O, and (CF3CF2SO2)2O.
Preferably, step (A) of our process is carried out by contacting the reaction mixture of the compound of formula (II) and the dehydrating agent with an additional agent selected from the group consisting of a Lewis acid or a super acid. Non-limitative examples of Lewis acids include AlCl3, FeCl3, ZnCl2, AlBr3, ZnBr2, TiCl4, and SnCl4. Of the foregoing, AlCl3, ZnCl2, FeCl3, SnCl4, and ZnBr2 are particularly preferred. Non-limitative examples of super acids include CF3SO3H, 
and HF/BF3. Of the foregoing super acids, CF3SO3H is particularly preferred. The contacting by the Lewis acid or the super acid may be accomplished by adding it prior to, contemporaneously with, or after the time at which the dehydrating agent is brought into contact with the compound of formula (II). Particularly preferred combinations of dehydrating agents and Lewis acids or super acids include P2O5/CF3SO3H, PCl5/AlCl3, POCl3/ZnCl2, PCl/FeCl3, PCl/SnCl4, and POCl3/ZnBr2.
When a dehydrating agent other than an anhydride is used in step (A), preferably the dehydrating agent is used in amounts ranging from 1 to 20 equivalents, more preferably, 1 to 10 equivalents, most preferably, 1.0 to 8.0 equivalents. When the dehydrating agent is an anhydride of a super acid, it is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably 1.0 to 5.0 equivalents, most preferably, 1.2 to 2.0 equivalents. When a Lewis acid is used in addition to the dehydrating agent, the Lewis acid is preferably used in amounts ranging from 1 to 20 equivalents, more preferably 1.5 to 10 equivalents, most preferably 2 to 5 equivalents. When a super acid is used in addition to the dehydrating agent, the super acid is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably, 1 to 5 equivalents, most preferably, 2 to 4 equivalents.
Step (A) is preferably carried out at a temperature of 10 to 120xc2x0 C., more preferably, 15 to 90xc2x0 C., most preferably 20 to 90xc2x0 C. The time for reaction ranges from 1 to 60 hours, preferably 2 to 40 hours, most preferably 5 to 35 hours.
The imine formed in step (A) is preferably hydrolyzed by adding water, preferably in an amount ranging from 1 to 10 volumes of the amide of formula (II), more preferably 1.5 to 7 volumes, most preferably 2 to 5 volumes. The hydrolysis is preferably carried out at a temperature of from 20 to 120xc2x0 C., more preferably from 30 to 100xc2x0 C., most preferably from 40 to 80xc2x0 C.
Preferably, steps (A) and (B) are carried out in an aprotic organic solvent. The aprotic organic solvent is preferably selected from dichloroethane, methylene chloride, benzene, and halogenated aromatic solvents, e.g., chlorobenzene, dichlorobenzene trichlorobenzene, and trifluoromethylbenzene.
The starting compounds of formula (II) may be prepared as shown in the following scheme: 
As shown in the scheme above (wherein RA, RB, RC, RD, RE, and R5 are as defined previously), the pyridine compound 1 is reacted with NH2R5 in the presence of a palladium catalyst, (e.g., Pd(OAc)2/dipyridyl or (Ph3P)2PdCl2), carbon monoxide, and a base, in a suitable solvent (e.g., tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), dimethylformamide (xe2x80x9cDMFxe2x80x9d), acetonitrile (CH3CN) and toluene, or combinations thereof, most preferably, CH3CN) at a temperature of about 35xc2x0 to 100xc2x0 C., preferably about 55xc2x0 C., and a pressure of about 5 psi to 500 psi, preferably about 50 to 150 psi, to form amide compound 2. Non-limitative examples of suitable bases for the foregoing reaction include C1 to C10 alkyl amines, such as triethylamine, tri-n-butylamine and 1,8-diazabicyclo-[5.4.0]undec-7-ene (xe2x80x9cDBUxe2x80x9d), and inorganic bases such as K2CO3, Na2CO3, Na2HPO4 and NaOH. Preferably, the base is selected from K2CO3, DBU, and triethylamine, with DBU being preferred for use with Pd(OAc)2/dipyridyl, and triethylamine being preferred for use with (Ph3P)2PdCl2. Amide compound 2 is reacted with compound 3 in the presence of a strong base (e.g., lithium diisopropylamide (xe2x80x9cLDAxe2x80x9d), n-butyl lithium, lithium hexamethyldisilylamide, or sodium amide, preferably LDA or n-butyl lithium) in a suitable solvent, e.g., THF, at a temperature of about xe2x88x9250xc2x0 C. to xe2x88x9220xc2x0 C., preferably about xe2x88x9230xc2x0 C. to xe2x88x9220xc2x0 C. to form the compound of formula (II).
Alternatively,the amide compound 2 may be prepared as shown in the scheme below: 
Picolinic acid compound 4 is reacted with an organic base, e.g., triethylamine, followed by an acid chloride, e.g., pivaloyl chloride or a chloroformate, e.g., C2H5OCOCl in a suitable solvent such as dichloromethane at a temperature of about xe2x88x9230xc2x0 C. to 0xc2x0 C. to give a mixed anhydride. To the mixture is added NH2R5 at a temperature of xe2x88x9230xc2x0 C. to 0xc2x0 C. either neat or as a solution in a suitable solvent to form amide compound 2.
The process for preparing compounds of formula (III) from compounds of formula (IV) is carried out by reacting the compound of formula (IV) with NH2R5 in the presence of a palladium catalyst, carbon monoxide, a base, and an ether selected from the group consisting of: ethylene glycol dimethyl ether (i.e., CH3OCH2CH2OCH3); 2-methoxyethyl ether (i.e, CH3OCH2CH2OCH2CH2OCH3); and triethylene glycol dimethyl ether (i.e, CH3OCH2CH2OCH2CH2OCH2CH2OCH3). X is preferably Br, Cl or F, most preferably, Br, and R5 is preferably phenyl, 4-methoxyphenyl, 4-chlorophenyl, or 3-chlorophenyl. Non-limitative examples of palladium catalysts that may be used in this process, include Pd(OAc)2, PdCl2, (PPh3)2PdCl2, PdBr2, and (PPh3)4Pd. Pd(OAc)2 and PdCl2 are particularly preferred. This process is preferably carried out at at a temperature of about 35xc2x0 C. to 120xc2x0 C., preferably about 40 to 100xc2x0 C., most preferably about 45 to 90xc2x0 C., and a pressure of about 5 psi to 500 psi, preferably about 30 to 150 psi, most preferably about 40 to 100 psi. Non-limitative examples of suitable bases for this process include C1 to C10 alkyl amines, such as diisopropylethylamine, diisopropylbenzylamine, tri-n-butylamine, triisopropylamine, triethylamine, t-butylamine and 1,8-diazabicyclo-[5.4.0]undec-7-ene (xe2x80x9cDBUxe2x80x9d), and inorganic bases such as K2CO3, KHCO3, Na2CO3, NaHCO3, Na3PO3, Na2HPO4, and NaOH. Preferably, the base is selected from K2CO3, DBU, triethylamine, and diisopropylethylamine, and most preferably, is selected from DBU and diisopropylethylamine. Preferably, this process is carried out in a solvent in addition to the ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether. Non-limitative examples of suitable solvents include toluene, chlorobenzene, dichlorobenzene, acetonitrile, trifluoromethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, and xylene, with toluene, and chlorobenzene being particularly preferred. Because the ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether functions as a ligand for the palladium catalyst, this process can be carried out without having to use dipyridyl as a ligand. The amount of NH2R5 used preferably ranges from 0.9 to 5 equivalents, more preferably from 1.0 to 3 equivalents, most preferably from 1.1 to 1.5 equivalents. The amount of base preferably ranges from 0.8 to 10 equivalents, more preferably from 1.0 to 5 equivalents, most preferably from 1.2 to 2.0 equivalents. The amount of ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether is preferably from 0.2 to 5.0 volumes of 2,5-dibromo-3-methylpyridne used, more preferably from 0.4 to 2.0 volumes, most preferably from 0.5 to 1.5 volumes. The amount of additional solvent (e.g., toluene or chlorobenzene) preferably ranges from 1.0 to 20 volumes of the 2,5-dibromo-3-methylpyridine used, more preferably from 1.5 to 10 volumes, most preferably from 2 to 5 volumes.
The starting materials used in the foregoing processes, i.e., compound 1, NH2R5, compound 3, and compound 4, are known in the art or can readily be prepared by one skilled in the art.